The ras oncogenes are activated through mutation and their translation products, the Ras proteins, play an important role in transformation of normal cells to cancer cells. Active ras oncogenes are observed in many types of cancer such as colorectal cancer and pancreatic cancer, reportedly in about 25% of human cancers. Accordingly, suppression of activation of the ras oncogenes or inhibition of the function of their products, the Ras protein, leads to prevention of carcinogenesis and is expected to produce an antitumor effect.
On the other hand, it has been revealed recently that the Ras proteins require their farnesylation in order to function and that inhibition of farnesylation prevents the Ras proteins from localizing on cell membranes and thus blocks carcinogenic transformation of cells. The activation of the Ras oncoproteins can be depressed by inhibiting protein-farnesyltransferase (PFT), the enzyme which catalyses farnesylation of the Ras proteins. Since the enzyme is involved in farnesylation of a limited number of proteins in the body, PFT inhibitors are promising as safe and selective antitumor agents. From this standpoint, a number of PFT inhibitors have been developed recently [Cell, vol. 57, 1167-1177 (1989); Proc. Natl. Acad. Sci, vol. 86, 8323-8327 (1989); Proc. Natl. Acad, Sci, vol. 90, 2281-2285 (1993); Science, vol. 245, 379-385 (1989); Science, vol. 260, 1934-1937 (1993); Science, vol. 260, 1937-1942 (1993); J. Biol. Chem., vol. 266, 15575-15578 (1991); J. Antibiotics, vol. 46, 222-227 (1993); Japanese Unexamined Patent Publication JP-A-5-201869; Japanese Unexamined Patent Publication JP-A-5-213992].
Recent study by the present inventors demonstrated that these PFT inhibitors can block the reactivation of static viruses by suppressing development of matured Ras proteins and are useful as anti-AIDS (HIV) agents (Japanese Patent Application JP6-331691).
However, in order to development them as drugs, there still remain problems that most of these PFT inhibitors have low activities in cells and do not have sufficient effect in vivo.
It is reported that agents which decrease farnesyl pyrophosphate in vivo, especially those which inhibit biosynthesis of farnesyl pyrophosphate such as hydroxymethylglutaryl CoA reductase (HMG CoA reductase) inhibitors are expected to exert antitumor effect by suppressing the functioning of the Ras oncoproteins [J. Biol Chem., vol. 265, 19937-19941 (1990)]. However, these agents exhibit quite insufficient antitumor activities when they are used alone.